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Effect of 12-O-tetradecanoylphorbol-13-acetate-induced psoriasis-like skin lesions on systemic inflammation and atherosclerosis in hypercholesterolaemic apolipoprotein E deficient mice.

Madsen M, Hansen PR, Nielsen LB, Hartvigsen K, Pedersen AE, Christensen JP, Aarup A, Pedersen TX - BMC Dermatol. (2016)

Bottom Line: Systemic effects of the topical application of TPA were demonstrated by increased plasma concentration of serum amyloid A and splenic immune modulation, respectively.TPA-induced psoriasis-like skin inflammation in atherosclerosis-prone ApoE(-/-) mice evoked systemic immune-inflammatory effects, but did not affect atherogenesis.The results may question the role of psoriasis-induced inflammation in the pathogenesis of atherosclerosis in psoriasis patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

ABSTRACT

Background: Risk of cardiovascular disease is increased in patients with psoriasis, but molecular mechanisms linking the two conditions have not been clearly established. Lack of appropriate animal models has hampered generation of new knowledge in this area of research and we therefore sought to develop an animal model with combined atherosclerosis and psoriasis-like skin inflammation.

Methods: Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) was applied to the ears twice per week for 8 weeks in atherosclerosis-prone apolipoprotein E deficient (ApoE(-/-)) mice.

Results: TPA led to localized skin inflammation with increased epidermal thickness, infiltration of inflammatory-like cells and augmented tissue interleukin-17F levels. Systemic effects of the topical application of TPA were demonstrated by increased plasma concentration of serum amyloid A and splenic immune modulation, respectively. However, atherosclerotic plaque area and composition, and mRNA levels of several inflammatory genes in the aortic wall were not significantly affected by TPA-induced skin inflammation.

Conclusions: TPA-induced psoriasis-like skin inflammation in atherosclerosis-prone ApoE(-/-) mice evoked systemic immune-inflammatory effects, but did not affect atherogenesis. The results may question the role of psoriasis-induced inflammation in the pathogenesis of atherosclerosis in psoriasis patients.

No MeSH data available.


Related in: MedlinePlus

Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) induces local skin inflammation with increased skin thickness and interleukin (IL)-17F levels. a Representative photos illustrating the red and scaly appearance of ears after TPA application as compared to control ears, and representative hematoxylin and eosin-stained ear cross-sections at 10× magnification. Scale bar = 200 μm. TPA led to epidermal hyperproliferation (star) and dermal inflammation (arrow). b Ear thickness (mm) was measured twice weekly in ApoE−/− mice after TPA or vehicle application. Data from two separate, but similar studies with vehicle or TPA application on both ears were included; study 1: n = 5–7/group (unfilled circle: control, filled circle: TPA), study 2: n = 15/group (unfilled triangle: control, filled triangle: TPA). The depicted values in b are mean ± SD, i.e., mean value of right and left ear for each mouse. p < 0.001, control vs. TPA at all time points except at baseline; multiple t-test corrected for multiple comparisons was applied. c Measurement of interleukin IL-17F, IL-12, and keratinocyte-derived cytokine (KC) in ear tissue homogenates after 8 weeks of TPA or vehicle application in study 1. Data is depicted as pg cytokine per mg total protein (median values, unpaired non-parametric t-test)
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Fig1: Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) induces local skin inflammation with increased skin thickness and interleukin (IL)-17F levels. a Representative photos illustrating the red and scaly appearance of ears after TPA application as compared to control ears, and representative hematoxylin and eosin-stained ear cross-sections at 10× magnification. Scale bar = 200 μm. TPA led to epidermal hyperproliferation (star) and dermal inflammation (arrow). b Ear thickness (mm) was measured twice weekly in ApoE−/− mice after TPA or vehicle application. Data from two separate, but similar studies with vehicle or TPA application on both ears were included; study 1: n = 5–7/group (unfilled circle: control, filled circle: TPA), study 2: n = 15/group (unfilled triangle: control, filled triangle: TPA). The depicted values in b are mean ± SD, i.e., mean value of right and left ear for each mouse. p < 0.001, control vs. TPA at all time points except at baseline; multiple t-test corrected for multiple comparisons was applied. c Measurement of interleukin IL-17F, IL-12, and keratinocyte-derived cytokine (KC) in ear tissue homogenates after 8 weeks of TPA or vehicle application in study 1. Data is depicted as pg cytokine per mg total protein (median values, unpaired non-parametric t-test)

Mentions: To induce psoriasis-like skin inflammation, hypercholesterolaemic ApoE−/− mice received twice weekly topical applications on both ears of either TPA or vehicle (control), for 8 weeks. TPA led to a skin reaction characterized by scaly skin and redness (Fig. 1a), and by a marked increase in ear thickness throughout the application period (p < 0.001 at all time points after baseline, TPA vs. control, Fig. 1b). The ear thickness in control mice was not affected by vehicle application. Histological examination of hematoxylin and eosin-stained ear cross-sections revealed that TPA induced epidermal thickening and local inflammation as assessed by the presence of inflammatory cells in the dermis (Fig. 1a). To investigate whether the TPA-induced histological features were accompanied by changes in local levels of inflammatory mediators, we measured protein levels of selected cytokines in ear lysates. Levels of IL-17F were significantly higher in ear lysates from TPA-treated mice as compared to those from control mice (16.2 [12.1–24.1] pg/mg total protein vs. 0 [0.0–0.5] pg/mg total protein, p = 0.003, Fig. 1c), indicating that topical TPA application induced a local immune response with infiltration of IL-17F producing cells. We found no difference in protein levels of IL-12 and KC. Protein levels of the cytokines IL-1β, −2, −4, −5, −6, −10, −12p70, −22, and IFNγ, and TNFα were below the ELISA detection limits in all ear lysates.Fig. 1


Effect of 12-O-tetradecanoylphorbol-13-acetate-induced psoriasis-like skin lesions on systemic inflammation and atherosclerosis in hypercholesterolaemic apolipoprotein E deficient mice.

Madsen M, Hansen PR, Nielsen LB, Hartvigsen K, Pedersen AE, Christensen JP, Aarup A, Pedersen TX - BMC Dermatol. (2016)

Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) induces local skin inflammation with increased skin thickness and interleukin (IL)-17F levels. a Representative photos illustrating the red and scaly appearance of ears after TPA application as compared to control ears, and representative hematoxylin and eosin-stained ear cross-sections at 10× magnification. Scale bar = 200 μm. TPA led to epidermal hyperproliferation (star) and dermal inflammation (arrow). b Ear thickness (mm) was measured twice weekly in ApoE−/− mice after TPA or vehicle application. Data from two separate, but similar studies with vehicle or TPA application on both ears were included; study 1: n = 5–7/group (unfilled circle: control, filled circle: TPA), study 2: n = 15/group (unfilled triangle: control, filled triangle: TPA). The depicted values in b are mean ± SD, i.e., mean value of right and left ear for each mouse. p < 0.001, control vs. TPA at all time points except at baseline; multiple t-test corrected for multiple comparisons was applied. c Measurement of interleukin IL-17F, IL-12, and keratinocyte-derived cytokine (KC) in ear tissue homogenates after 8 weeks of TPA or vehicle application in study 1. Data is depicted as pg cytokine per mg total protein (median values, unpaired non-parametric t-test)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig1: Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) induces local skin inflammation with increased skin thickness and interleukin (IL)-17F levels. a Representative photos illustrating the red and scaly appearance of ears after TPA application as compared to control ears, and representative hematoxylin and eosin-stained ear cross-sections at 10× magnification. Scale bar = 200 μm. TPA led to epidermal hyperproliferation (star) and dermal inflammation (arrow). b Ear thickness (mm) was measured twice weekly in ApoE−/− mice after TPA or vehicle application. Data from two separate, but similar studies with vehicle or TPA application on both ears were included; study 1: n = 5–7/group (unfilled circle: control, filled circle: TPA), study 2: n = 15/group (unfilled triangle: control, filled triangle: TPA). The depicted values in b are mean ± SD, i.e., mean value of right and left ear for each mouse. p < 0.001, control vs. TPA at all time points except at baseline; multiple t-test corrected for multiple comparisons was applied. c Measurement of interleukin IL-17F, IL-12, and keratinocyte-derived cytokine (KC) in ear tissue homogenates after 8 weeks of TPA or vehicle application in study 1. Data is depicted as pg cytokine per mg total protein (median values, unpaired non-parametric t-test)
Mentions: To induce psoriasis-like skin inflammation, hypercholesterolaemic ApoE−/− mice received twice weekly topical applications on both ears of either TPA or vehicle (control), for 8 weeks. TPA led to a skin reaction characterized by scaly skin and redness (Fig. 1a), and by a marked increase in ear thickness throughout the application period (p < 0.001 at all time points after baseline, TPA vs. control, Fig. 1b). The ear thickness in control mice was not affected by vehicle application. Histological examination of hematoxylin and eosin-stained ear cross-sections revealed that TPA induced epidermal thickening and local inflammation as assessed by the presence of inflammatory cells in the dermis (Fig. 1a). To investigate whether the TPA-induced histological features were accompanied by changes in local levels of inflammatory mediators, we measured protein levels of selected cytokines in ear lysates. Levels of IL-17F were significantly higher in ear lysates from TPA-treated mice as compared to those from control mice (16.2 [12.1–24.1] pg/mg total protein vs. 0 [0.0–0.5] pg/mg total protein, p = 0.003, Fig. 1c), indicating that topical TPA application induced a local immune response with infiltration of IL-17F producing cells. We found no difference in protein levels of IL-12 and KC. Protein levels of the cytokines IL-1β, −2, −4, −5, −6, −10, −12p70, −22, and IFNγ, and TNFα were below the ELISA detection limits in all ear lysates.Fig. 1

Bottom Line: Systemic effects of the topical application of TPA were demonstrated by increased plasma concentration of serum amyloid A and splenic immune modulation, respectively.TPA-induced psoriasis-like skin inflammation in atherosclerosis-prone ApoE(-/-) mice evoked systemic immune-inflammatory effects, but did not affect atherogenesis.The results may question the role of psoriasis-induced inflammation in the pathogenesis of atherosclerosis in psoriasis patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

ABSTRACT

Background: Risk of cardiovascular disease is increased in patients with psoriasis, but molecular mechanisms linking the two conditions have not been clearly established. Lack of appropriate animal models has hampered generation of new knowledge in this area of research and we therefore sought to develop an animal model with combined atherosclerosis and psoriasis-like skin inflammation.

Methods: Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) was applied to the ears twice per week for 8 weeks in atherosclerosis-prone apolipoprotein E deficient (ApoE(-/-)) mice.

Results: TPA led to localized skin inflammation with increased epidermal thickness, infiltration of inflammatory-like cells and augmented tissue interleukin-17F levels. Systemic effects of the topical application of TPA were demonstrated by increased plasma concentration of serum amyloid A and splenic immune modulation, respectively. However, atherosclerotic plaque area and composition, and mRNA levels of several inflammatory genes in the aortic wall were not significantly affected by TPA-induced skin inflammation.

Conclusions: TPA-induced psoriasis-like skin inflammation in atherosclerosis-prone ApoE(-/-) mice evoked systemic immune-inflammatory effects, but did not affect atherogenesis. The results may question the role of psoriasis-induced inflammation in the pathogenesis of atherosclerosis in psoriasis patients.

No MeSH data available.


Related in: MedlinePlus